Our goal is to better understand the role of gene interactions (epistasis) in producing complex phenotypes using a combination of theoretical models, quantitative genetics, molecular genetics, and experimental populations of flour beetles, genus Tribolium. Our specific goals are to isolate, map, and compare the genes that interact to cause a reduction of mating success, viability, and fertility in (1) inter-population crosses, with those causing fitness reduction in (2) inter-specific crosses. Incompatibility genes interact in the same way as those genes causing human genetic diseases, cancer susceptibility, and pathogen resistance. First, we will investigate the genetic basis of (1) pre-zygotic male infertility; and, (2) post-zygotic reproductive isolation observed in inter-population crosses of T. castaneum. Our statistical genetic studies indicate that maternal effects and epistasis cause reduced viability and fertility fitness in F2 and backcrosses between 3 pairs of populations from collected from Central America, South America, and Africa. However, because statistical genetic methods average positive and negative effects of different gene combinations, we will use a microsatellite map of the Tribolium genome to dissect the average effects of gene interactions into their single locus components. Because each of 3 pairs of partially isolated populations is fully inter-fertile with a laboratory strain, we will create recombinant congenic lines by reciprocal backcrosses to the lab strain in order to isolate those genes in each of the two backgrounds, which, when combined-by inter-population crosses, cause reproductive incompatibility. Second. we will identify the genes in T. castaneum, which interact with one another and with genes from T. freemani, to cause hybrid male deformities and hybrid male inviability in inter-specific crosses. We will compare the sets of genes reducing fitness in inter-population crosses in T. castaneum with those diminishing the fitness of its inter-specific hybrids with T. freemani. We can determine whether the genes interacting to reduce the fitness of T. castaneum inter-population crosses are a subset of those reducing hybrid fitness in inter-specific crosses. The latter must include some gene differences accumulated after speciation. Alternatively, the barrier to gene exchange between T. castaneum and T. freemani may represent either, a sample of the genes posing incipient barriers, to gene exchange between populations of T. castaneum, or it may be unique.